Efforts to synthesize biologically active natural products provide a powerful impetus for the development of new synthetic methods. We have identified four natural products as synthetic targets for the next grant period. SCH 351448 is a C2 symmetric diolide. It is the first small-molecule activator of the LDL receptor promoter and has the potential to decrease serum LDL level by increasing LDL uptake. The second target is amphidinol 3, which demonstrates potent antifungal activity against Aspergillus niger. Maoecrystal V is a very interesting modified ent-kauranoside norditerpene isolated from a Chinese medicinal shrub that shows very potent toxicity against one human cancer cell line but is almost nontoxic to other human cell lines. Sporolide A is a complex macrocycle probably derived from an enediyne "presporolide" natural product. It has a very unusual structure and may be derived from a biosynthetic ortho-quinone Diels-Alder reaction. These four synthetic targets will be approached with a variety of synthetic methods and strategies under development in my laboratory. The goal of this proposal is to develop syntheses of these complex natural products using new synthetic methods and synthetic strategies. The symmetric diolide SCH 351448 will be assembled using a Ca2+ template to direct the dimerization and cyclization. Complex alkyllithium and organozinc reagents are key intermediates in the proposed construction of amphidinol 3. Sequential intramolecular Heck reaction and intermolecular Diels-Alder reaction will be used to construct the two adjacent quaternary centers in maoecrystal V. An ortho-quinone Diels-Alder reaction will be used in the synthesis of sporolide A. Each one of these syntheses is designed to be highly convergent and to advance the state of modern synthetic chemistry. PUBLIC HEALTH RELEVANCE Synthetic chemistry is the technology underlying modern drug development. This proposal focuses on the synthesis of complex natural products and the development of new synthetic methods to apply to these problems. These new synthetic methods and more general synthetic strategies can be used by scientists worldwide to develop new drug candidates to treat human diseases. The beneficial impact of modern drug development on human health is second only to immunization. [unreadable] [unreadable] [unreadable]